It has been apparent for decades that the study of human diseases, especially well defined genetic diseases, are powerful tools in the elucidation of normal physiologic events. This is most evident in the case of the primary immune deficiency diseases. Characterization of specific immune deficiency states has led to remarkable advances in immunology, catalyzing greater understanding of these diseases, and sparking the development of novel diagnostic techniques and targeted treatments. Studies of primary human B cell defects have led to an appreciation of specific stages of B cell development. Commitment to the B cell lineage occurs early in lymphogenesis with selected gene rearrangements in Ig heavy chain genes which initiates the process of antigen recognition, a hallmark of adaptive immunity. Further maturation of B cells is characterized by expansion, differentiation, trafficking to specific compartments in peripheral lymph nodes, and selection of appropriate antigen receptors and finally, the generation of B cell memory. Coupled with the expansion or B cell populations, is the requirement for deletion of self-reactive clones. All of these events are intertwined, but the nature of these interactions is incompletely understood. The overall hypothesis governing this Program Project Grant is that selected cellular and micro-environmental influences are critical to normal B cell development and that defects in any of these processes can result in a form of immune deficiency. This Program Project selects four specific stages of B cell immunity to investigate, using unique primary immune deficiencies as model systems. These four stages and the related themes are: Project 1: Combined immune deficiencies: links to repair defects; Project 2: Investigating blocks to B cell memory; Project 3: Chemokine signaling defects in human immune deficiency; Project 4: Loss of B cell tolerance in primary immune deficiency. The development of normal protective immunity is essential for understanding disease prevention, transplantation, and autoimmune disease; how these immune responses are developed and controlled, are still poorly elucidated. At Mount Sinai we have a unique and valuable resource in our Primary Immune Deficiency Program; this allows for careful study of selected stages of human B cell biology, the subject of this Program Project Grant.